Project Abstract Parkinson disease (PD) is caused by progressive and substantial loss of dopaminergic neurons in the midbrain. Although PD symptoms can be alleviated by dopamine replenishment therapy, the available treatments cannot protect the neurons at risk or prevent the disease from progression because we have a limited knowledge on PD pathogenesis. Recent advance in genetic and epidemiological studies suggests a multifactorial etiology for PD. Besides aging, genetic and environmental factors are associated with the risk for PD. In animal models, exposure to the environmental toxin paraquat causes permanent and accumulative damage to dopaminergic system. Most PD cases have no causative mutation in the identified PD genes, but there may be epigenetic modifications to neuron-protective genes during aging process. How PD risky factors interact to cause the disease remains to be elucidated. One possible pathogenesis for PD is that the disease is caused by early exposure to environmental toxicants in combination with subsequent dysfunction of neuron-protective genes during aging process: early exposure to environmental toxins may reduce the threshold of developing PD; later dysfunction of one or more neuron-protective genes may accelerate the neuronal death, cross the reduced threshold for PD onset, and result in Parkinsonism. The genetic models for PD are mostly generated by constitutive mutation of targeted genes and thus cannot model temporal dysfunction of a gene later in life. To test this hypothetic pathogenesis of PD, we have created conditionally mutated mice to produce temporal and partial dysfunction of the targeted genes after the animals are exposed to environmental toxin in their early lives. We will use paraquat as a PD-related environmental toxin and PINK1 as a PD-linked gene. Dopamine likely plays an important role in PD pathogenesis because disturbance in dopamine homeostasis causes severely pathobiological conditions leading to neuronal death. Therefore, we will study the neuron-protective gene VMAT2 since VMAT2 plays a major role in dopamine homeostasis. This proposal will test how early exposure to environmental toxin superimposes deleterious effect on phenotypic expression subsequent to disturbance in dopamine homeostasis in later life, subsequent to later dysfunction of the PINK1 gene, or subsequent to later dysfunction of two neuron-protective genes. Results from this study will advance our understanding of PD pathogenesis and provide guidance to the development of therapeutic strategies for treating this devastating disease.